Zika-Associated Birth Defects Reported in Pregnancies With Laboratory Evidence of Confirmed or Possible Zika Virus Infection

U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018

Nicole M. Roth, MPH; Megan R. Reynolds, MPH; Elizabeth L. Lewis, MPH; Kate R. Woodworth, MD; Shana Godfred-Cato, DO; Augustina Delaney, PhD; Amanda Akosa, MPH; Miguel Valencia-Prado, MD; Maura Lash, MPH; Amanda Elmore, MPH; Peter Langlois, PhD; Salma Khuwaja, MD, DrPH; Aifili Tufa, PhD; Esther M. Ellis, PhD; Eirini Nestoridi, MD; Caleb Lyu, PhD; Nicole D. Longcore, MPH; Monika Piccardi, MS; Leah Lind, MPH; Sharon Starr, MSN; Loletha Johnson, MSN; Shea E. Browne, MS; Michael Gosciminski, MPH; Paz E. Velasco, MD; Fern Johnson-Clarke, PhD; Autumn Locklear, MSPH; Mary Chan, MPH; Jane Fornoff, DPhil; Karrie-Ann E. Toews, MPS; Julius Tonzel, MPH; Natalie S. Marzec, MD; Shelby Hale, MPH; Amy E. Nance, MPH; Teri' Willabus, MPH; Dianna Contreras; Sowmya N. Adibhatla, MPH; Lisa Iguchi, MPH; Emily Potts, MPH,; Elizabeth Schiffman, MPH; Katherine Lolley, MPH; Brandi Stricklin; Elizabeth Ludwig, MD; Helentina Garstang, DCHMS; Meghan Marx; Emily Ferrell, MPH; Camille Moreno-Gorrin, MS; Kimberly Signs, DVM; Paul Romitti, PhD; Vinita Leedom, MPH; Brennan Martin, MPH; Louisa Castrodale, DVM; Amie Cook, MPH; Carolyn Fredette, MPH; Lindsay Denson, MS; Laura Cronquist; John F. Nahabedian III, MS; Neha Shinde, MPH; Kara Polen, MPH; Suzanne M. Gilboa, PhD; Stacey W. Martin, MSc; Janet D. Cragan, MD; Dana Meaney-Delman, MD; Margaret A. Honein, PhD; Van T. Tong, MPH; Cynthia A. Moore, MD, PhD

Disclosures

Morbidity and Mortality Weekly Report. 2022;71(3):73-79.

Abstract and Introduction

Introduction

Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities.^[1,2] The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate.^[3,4]This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015–March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

Abstract and Introduction
Discussion
References
Sidebar

*Maternal laboratory evidence of confirmed or possible Zika virus infection was defined as 1) Zika virus infection detected by a Zika virus RNA nucleic acid amplification test (NAAT) (e.g., reverse transcription–polymerase chain reaction [RT-PCR]) on any maternal, placental, fetal, or infant specimen (referred to as positive Zika virus NAAT) or 2) detection of recent Zika virus infection or recent unspecified flavivirus infection by serologic tests on a maternal, fetal, or infant specimen (i.e., either positive or equivocal Zika virus immunoglobulin M [IgM] and Zika virus plaque reduction neutralization test [PRNT] titer ≥10, regardless of dengue virus PRNT value; or negative Zika virus IgM, and positive or equivocal dengue virus IgM, and Zika virus PRNT titer ≥10, regardless of dengue virus PRNT titer). Infants with positive or equivocal Zika virus IgM are included, provided a confirmatory PRNT has been performed on a maternal or infant specimen. The use of PRNT for confirmation of Zika virus infection, including during pregnancy, in women and infants, is not routinely recommended in Puerto Rico; dengue virus is endemic and cross-reactivity is likely to occur in most cases (https://www.cdc.gov/zika/laboratories/lab-guidance.html). In Puerto Rico, detection of a positive Zika virus IgM result in a pregnant woman, fetus, or infant (within 48 hours after delivery) was considered sufficient to indicate possible Zika virus infection.
^†U.S. territories in USZPIR are American Samoa, Puerto Rico, and the U.S. Virgin Islands; freely associated states are Federated States of Micronesia and the Marshall Islands.
^§Infants and children in Puerto Rico and the U.S. Virgin Islands are followed through age 5 years; infants and children in U.S. states and DC, and U.S. territories and freely associated states are followed through age 3 years.
^¶ https://www.researchsquare.com/article/rs-1189991/v1
**Includes maternal, placental, fetal, or infant laboratory evidence of Zika virus infection based on the presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR).
^††Pregnancy losses include spontaneous abortions, terminations, stillbirths, and pregnancy losses not specified. Information from prenatal or postnatal imaging and autopsy were used to determine presence of Zika-associated birth defects, although pregnancy losses often had less information reported and frequently lacked postnatal imaging that could verify prenatal findings and might identify additional abnormalities.
^§§45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.
^¶¶Signs and symptoms included fever, arthralgia, conjunctivitis, rash, and other clinical signs or symptoms that are consistent with Zika virus disease.
***Zika virus infections that occurred during the periconceptual period, which is defined as 4 weeks before last menstrual period, are included in the first trimester.

Table 1. Frequency of Zika-associated birth defects,* by selected characteristics among live-born infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection — U.S. Zika Pregnancy and Infant Registry, December 1, 2015–March 31, 2018
Characteristic	From pregnancies with laboratory evidence of confirmed or possible Zika virus infection^†		From pregnancies with positive Zika virus NAAT result^§
Characteristic	No./Total no.	% (95% CI)	No./Total no.	% (95% CI)
Total	315/6,799	4.6 (4.1–5.2)	138/2,257	6.1 (5.1–7.2)
Location of birth
U.S. states and DC	124/2,288	5.4 (4.5–6.5)	38/374	10.2 (7.2–14.0)
U.S. territories and freely associated states^¶	191/4,511	4.2 (3.7–4.9)	100/1,883	5.3 (4.3–6.5)
Trimester with first evidence of exposure,^††**
1st^§§	108/2,121	5.1 (4.2–6.2)	43/539	8.0 (5.8–10.8)
2nd	107/2,495	4.3 (3.5–5.2)	62/1,028	6.0 (4.6–7.7)
3rd	82/2,039	4.0 (3.2–5.0)	25/657	3.8 (2.5–5.6)
Maternal symptoms^¶¶,***
Signs/Symptoms of Zika virus disease	126/2,379	5.3 (4.4–6.3)	92/1,596	5.8 (4.7–7.1)
No signs/symptoms of Zika virus disease	186/4,382	4.2 (3.7–4.9)	46/661	7.0 (5.1–9.3)
Examinations reported
Neuroimaging	258/4,086	6.3 (5.6–7.1)	120/1,595	7.5 (6.2–9.0)
Ophthalmology	167/2,456	6.8 (5.8–7.9)	79/1,072	7.4 (5.8–9.2)

Abbreviations: DC = District of Columbia; NAAT = nucleic acid amplification test; RT-PCR = reverse transcription–polymerase chain reaction; USZPIR = U.S. Zika Pregnancy and Infant Registry.
*Zika-associated birth defects include selected congenital brain anomalies (intracranial calcifications, cerebral or cortical atrophy, abnormal cortical gyral patterns, corpus callosum abnormalities, cerebellar abnormalities, porencephaly, hydranencephaly, or ventriculomegaly/hydrocephaly); selected congenital eye anomalies (microphthalmia or anophthalmia; coloboma; cataract; intraocular calcifications; chorioretinal anomalies involving the macula, excluding retinopathy of prematurity; and optic nerve atrophy, pallor, and other optic nerve abnormalities); and/or microcephaly at birth (birth head circumference below the third percentile for infant sex and gestational age based on INTERGROWTH-21st online percentile calculator unless infants meet criteria of possible measurement inaccuracy. http://intergrowth21.ndog.ox.ac.uk/
^†Includes maternal, placental, or infant laboratory evidence of confirmed or possible Zika virus infection during pregnancy based on presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR), serologic evidence of a Zika virus infection, or serologic evidence of an unspecified flavivirus infection.
^§Includes maternal, placental, or infant laboratory evidence of confirmed Zika virus infection during pregnancy based on presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR).
^¶U.S. territories in USZPIR are American Samoa, Puerto Rico, and the U.S. Virgin Islands; freely associated states are Federated States of Micronesia and the Marshall Islands.
**Among pregnancies in which birth occurred in the U.S. states and DC, symptom onset date, travel dates to an endemic region, or date of earliest laboratory evidence of Zika virus infection were used to calculate trimester of exposure. Among pregnancies in which birth occurred in U.S. territories and freely associated states, symptom onset date or date of earliest laboratory evidence of Zika virus infection were used to calculate trimester of exposure.
^††Unknown trimester of exposure is not shown because of small cell sizes; 144 pregnancies were missing trimester of exposure.
^§§Zika virus infections that occurred during the periconceptual period, which is defined as 4 weeks before last menstrual period, are included in the first trimester of exposure.
^¶¶Maternal symptom status is not shown because of small cell sizes; 38 pregnancies were missing maternal symptom status.
***Signs and symptoms included fever, arthralgia, conjunctivitis, rash, and other clinical signs or symptoms that are consistent with Zika virus disease.

Table 2. Individual Zika-associated birth defects among live-born infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection — U.S. Zika Pregnancy and Infant Registry, December 1, 2015–March 31, 2018
Birth defect	No. of infants (%)
Birth defect	From pregnancies with laboratory evidence of confirmed or possible Zika virus infection* (n = 6,799)	From pregnancies with positive Zika virus NAAT result^† (n = 2,257)
Any Zika-associated birth defect^§	315 (4.6)	138 (6.1)
Brain abnormalities/Microcephaly^¶
Any brain abnormality/microcephaly	275 (4.0)	126 (5.6)
Microcephaly^**,††	214 (3.1)	100 (4.4)
Corpus callosum abnormalities	64 (0.9)	40 (1.8)
Intracranial calcifications	58 (0.9)	27 (1.2)
Abnormal cortical gyral patterns	56 (0.8)	29 (1.3)
Ventriculomegaly/Hydrocephaly	53 (0.8)	34 (1.5)
Cerebral or cortical atrophy	43 (0.6)	24 (1.1)
Cerebellar abnormalities	27 (0.4)	15 (0.7)
Fetal brain disruption sequence	12 (0.2)	10 (0.4)
Brainstem abnormalities	8 (0.1)	6 (0.3)
Porencephaly/Hydranencephaly	5 (0.1)	3 (0.1)
Eye abnormalities
Any eye abnormality	76 (1.1)	34 (1.5)
Chorioretinal atrophy, scarring, or pigmentary changes	47 (0.7)	25 (1.1)
Optic nerve abnormalities	34 (0.5)	13 (0.6)
Coloboma	7 (0.1)	5 (0.2)
Congenital cataract	7 (0.1)	3 (0.1)
Microphthalmia	5 (0.1)	1 (—)
Other brain and eye abnormality patterns
Multiple brain or eye abnormalities	110 (1.6)	55 (2.4)
Brain and eye abnormalities	36 (0.5)	22 (1.0)
One or more brain abnormalities only	239 (3.5)	104 (4.6)
One brain abnormality or microcephaly only	173 (2.5)	72 (3.2)
Microcephaly only^§§	144 (2.1)	58 (2.6)
Microcephaly only and SGA	98 (1.4)	37 (1.6)
One or more eye abnormalities only	40 (0.6)	12 (0.5)
One eye abnormality only	32 (0.5)	11 (0.5)

Abbreviations: NAAT = nucleic acid amplification test; RT-PCR = reverse transcription–polymerase chain reaction; SGA = small for gestational age.
*Includes maternal, placental, or infant laboratory evidence of confirmed or possible Zika virus infection during pregnancy based on presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR), serologic evidence of a Zika virus infection, or serologic evidence of an unspecified flavivirus infection.
^†Includes maternal, placental, or infant laboratory evidence of confirmed Zika virus infection during pregnancy based on presence of Zika virus RNA by a positive NAAT.
^§Zika-associated birth defects include selected congenital brain anomalies (intracranial calcifications, cerebral or cortical atrophy, abnormal cortical gyral patterns, corpus callosum abnormalities, cerebellar abnormalities, porencephaly, hydranencephaly, or ventriculomegaly/hydrocephaly); selected congenital eye anomalies (microphthalmia or anophthalmia; coloboma; cataract; intraocular calcifications; chorioretinal anomalies involving the macula, excluding retinopathy of prematurity; and optic nerve atrophy, pallor, and other optic nerve abnormalities); and/or microcephaly at birth (birth head circumference below the third percentile for infant sex and gestational age based on INTERGROWTH-21st online percentile calculator unless infants meet criteria of possible measurement inaccuracy. http://intergrowth21.ndog.ox.ac.uk/
^¶Among infants with brain abnormalities, microcephaly, or both, 24 (0.4%) and 11 (0.5%) infants also had arthrogryposis among pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively.
**Infants with birth head circumference below the third percentile based on INTERGROWTH-21st. http://intergrowth21.ndog.ox.ac.uk/
^††Among infants with microcephaly, 141 and 64 also had a birthweight below the 10th percentile (SGA) among pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively.
^§§Neuroimaging was available for 66.0% and 29.2% of infants with microcephaly only from pregnancies with laboratory evidence of confirmed or possible Zika virus infection during pregnancy and NAAT-confirmed Zika virus infection, respectively.

Authors and Disclosures

Nicole M. Roth, MPH¹, Megan R. Reynolds, MPH¹, Elizabeth L. Lewis, MPH¹, Kate R. Woodworth, MD¹, Shana Godfred-Cato, DO¹, Augustina Delaney, PhD², Amanda Akosa, MPH², Miguel Valencia-Prado, MD³, Maura Lash, MPH⁴, Amanda Elmore, MPH⁵, Peter Langlois, PhD⁶, Salma Khuwaja, MD, DrPH⁷, Aifili Tufa, PhD⁸, Esther M. Ellis, PhD⁹, Eirini Nestoridi, MD¹⁰, Caleb Lyu, PhD¹¹, Nicole D. Longcore, MPH¹², Monika Piccardi, MS¹³, Leah Lind, MPH¹⁴, Sharon Starr, MSN¹⁵, Loletha Johnson, MSN¹⁶, Shea E. Browne, MS¹⁷, Michael Gosciminski, MPH¹⁸, Paz E. Velasco, MD¹⁹, Fern Johnson-Clarke, PhD²⁰, Autumn Locklear, MSPH²¹, Mary Chan, MPH²², Jane Fornoff, DPhil²³, Karrie-Ann E. Toews, MPS²⁴, Julius Tonzel, MPH²⁵, Natalie S. Marzec, MD²⁶, Shelby Hale, MPH²⁷, Amy E. Nance, MPH²⁸, Teri' Willabus, MPH²⁹, Dianna Contreras³⁰, Sowmya N. Adibhatla, MPH³¹, Lisa Iguchi, MPH³², Emily Potts, MPH,³³, Elizabeth Schiffman, MPH³⁴, Katherine Lolley, MPH³⁵, Brandi Stricklin³⁶, Elizabeth Ludwig, MD³⁷, Helentina Garstang, DCHMS³⁸, Meghan Marx³⁹, Emily Ferrell, MPH⁴⁰, Camille Moreno-Gorrin, MS⁴¹, Kimberly Signs, DVM⁴², Paul Romitti, PhD⁴³, Vinita Leedom, MPH⁴⁴, Brennan Martin, MPH⁴⁵, Louisa Castrodale, DVM⁴⁶, Amie Cook, MPH⁴⁷, Carolyn Fredette, MPH⁴⁸, Lindsay Denson, MS⁴⁹, Laura Cronquist⁵⁰, John F. Nahabedian III, MS², Neha Shinde, MPH², Kara Polen, MPH¹, Suzanne M. Gilboa, PhD¹, Stacey W. Martin, MSc⁵¹, Janet D. Cragan, MD¹, Dana Meaney-Delman, MD¹, Margaret A. Honein, PhD¹, Van T. Tong, MPH¹ and Cynthia A. Moore, MD, PhD¹

¹Division of Birth Defects and Infant Disorders, National Center on Birth Defects and Developmental Disabilities, CDC; ²Eagle Global Scientific, LLC, San Antonio, Texas; ³Puerto Rico Department of Health; ⁴New York City Department of Health and Mental Hygiene, New York; ⁵Florida Department of Health; ⁶Texas Department of State Health Services; ⁷Houston Health Department, Houston, Texas; ⁸American Samoa Department of Health; ⁹U.S. Virgin Islands Department of Health; ¹⁰Massachusetts Department of Public Health; ¹¹Los Angeles County Department of Public Health, Los Angeles, California; ¹²New York State Department of Health; ¹³Maryland Department of Health; ¹⁴Pennsylvania Department of Health; ¹⁵Philadelphia Department of Public Health, Philadelphia, Pennsylvania; ¹⁶New Jersey Department of Health; ¹⁷Virginia Department of Health; ¹⁸Rhode Island Department of Health; ¹⁹Kosrae State Department of Health Services, Federated States of Micronesia; ²⁰District of Columbia Department of Health, Washington, DC; ²¹North Carolina Department of Health and Human Services; ²²Washington State Department of Health; ²³Illinois Department of Public Health; ²⁴Chicago Department of Public Health, Chicago, Illinois; ²⁵Louisiana Department of Health; ²⁶Colorado Department of Public Health and Environment; ²⁷Ohio Department of Health; ²⁸Utah Department of Health; ²⁹Georgia Department of Public Health; ³⁰Arizona Department of Health Services; ³¹Wisconsin Department of Health Services; ³²Oregon Health Authority; ³³Indiana Department of Health; ³⁴Minnesota Department of Health; ³⁵Tennessee Department of Health; ³⁶Arkansas Department of Health; ³⁷Nebraska Department of Health and Human Services; ³⁸Republic of the Marshall Islands Ministry of Health and Human Services; ³⁹South Dakota Department of Health; ⁴⁰Kentucky Department of Public Health; ⁴¹Delaware Health and Social Services; ⁴²Michigan Department of Health and Human Services; ⁴³University of Iowa College of Public Health, Iowa City, Iowa; ⁴⁴South Carolina Department of Health and Environmental Control; ⁴⁵Vermont Department of Health; ⁴⁶Alaska Department of Health and Social Services; ⁴⁷Kansas Department of Health and Environment; ⁴⁸New Hampshire Department of Health and Human Services; ⁴⁹Oklahoma State Department of Health; ⁵⁰North Dakota Department of Health; ⁵¹Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC.

Corresponding author
Nicole M. Roth, setnet@cdc.gov.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Amanda Elmore reports support from the Florida Birth Defects Registry, Surveillance, Intervention, and Referral to Services for Infants with Microcephaly or Other Adverse Outcomes linked with the Zika Virus in Florida. Jane Fornoff reports that she is vice-chair of the Illinois Department of Public Health's Institutional Review Board. Nicole D. Longcore reports grant support from Epidemiology and Laboratory Capacity for Infectious Diseases. Amy E. Nance reports that the is co-chair for Communication and Health Promotion of the National Birth Defect Prevention Network. Brennan Martin reports being a member-at-large for the National Birth Defect Prevention Network (2019). No other potential conflicts of interest were disclosed.